WHO guidance on first new TB treatment in five decades offers hope, emphasizes monitoring

WHO cites need to prevent new drug resistance, protect first treatment advance in more than 40 years

The World Health Organization’s release this week of interim policy guidelines on the use of bedaquiline for treatment of multidrug-resistant tuberculosis offers hope to patients and their physicians running out of options to treat the disease, but the document also highlights the need for more research, selective use, and vigilant roll out of the first new approach to TB treatment in nearly half a century.

The United States Food and Drug Administration granted accelerated approval to bedaquiline in December, but with caveats about limits in current knowledge of the safety of the drug, which has been associated with a heart rhythm irregularity. The interim guidance by the WHO based on Phase IIb clinical trials is considered necessary to ensure that the drug’s use is monitored carefully, as, the guidance states, “in the absence of interim guidance from WHO, uncontrolled and potentially irresponsible use of the drug may adversely affect TB care and control efforts overall – potentially prompting the emergence of bedaquiline resistance and the possible loss of the first new TB chemotherapeutic drug in over forty years.”

More than half a million people are diagnosed with MDR-TB every year. Less than half of MDR-TB patients started on treatment worldwide in 2009 successfully completed treatment, with 15 percent dying, and 28 percent lost to follow up, with adverse drug reactions being among the causes. Of 200 extensively drug-resistant TB patients in 14 countries, just a third completed treatment successfully, while more than a quarter of the patients died. Current drug-resistant TB treatment regimens are long, costly, and more toxic and less effective than drugs used to treat drug-susceptible TB.

Among the side effects to existing treatment for multidrug resistant tuberculosis is partial or complete hearing loss, and this side effect has not been associated with bedaquiline.

In January the WHO convened an expert group to develop interim policy recommendations based on an assessment of all available data from manufacturer Janssen and modeling work to assess the potential cost-effectiveness of implementation.

The group determined that bedaquiline may be added to a WHO-recommended treatment regimen for adult MDR-TB patients under the following conditions:

Patients be informed and involved in the decision to use bedaquiline

Additional caution in use for people with HIV, diabetes, other chronic illnesses, and with people reporting alcohol or drug use

That bedaquiline be used no more than six months and not be added alone to a failing regimen

That patients be tested, monitored, and clinically managed for cardiac arrhythmia, other conditions that could be affected by treatment including cardiac and liver disease

That country programs institute immediate reporting of adverse reactions, with patient groups actively involved in awareness and assessment of potentially harmful side effects from the medicine

Signs of potential drug-resistance be closely monitored

Resistance to other TB drugs be monitored according to WHO recommendations

The expert group expressed concern about the risk of adverse cardiac effects of bedaquiline use, particularly when used in combination with other MDR-TB drugs reported to have similar effects.

WHO’s interim guidance is a necessary step but leaves much to be done, cautioned Erica Lessem, of Treatment Action Group’s TB/HIV project. The drug has only been approved for use in the United States, and the manufacturer has only filed applications for approval of its use in a handful of other countries, she noted. More countries need to build up their program capacities to ensure that the drug is used properly, to meet concerns about safety and drug resistance.

Lessem also stressed the need for further research: “There are big research gaps on whether bedaquiline is appropriate for use by children, pregnant women, the elderly, and people with HIV on antiretrovirals, with hepatitis B or C, and/or who use drugs (including methadone and buprenorphine) and alcohol. For bedaquiline to be used safely and equitably, these questions need to be answered urgently.”